This project is concerned with exploring theoretical factors involved in mutagenesis and the initial steps in carcinogenesis. Recent experimental advances in the area of genetic engineering have provided new possibilities for studying the dependence of chemically induced mutational events on DNA sequence. We are using computer modeling to examine the physical chemical factors (charge distribution, chemical reactivity, and stereochemical and thermodynamic relationships) contributing to site specificity of chemical agents at the level of DNA damage. We are employing ab initio quantum chemical techniques to obtain charge distributions and geometric parameters on small systems, molecular mechanics and dynamics on larger systems (10 to 20- mer oligonucleotides) and computer graphics for analysis of predicted structures. Computing equipment used includes: the dual DEC 8650's at NIEHS, an office microvax-II, a Silicon Graphics 2400 IRIS workstation and the National Cancer Institute CRAY-XMP at Frederick, MD. Future emphases will be to characterize local structures of DNA sequences (native and chemically modified) that contain known hot spots from mammalian oncogenes and model bacterial systems.